The overall goals of this proposal are to understand the role of alpha-synuclein, parkin, DJ-1 and synphilin-1 in the pathogenesis and pathology of Parkinson's disease (PD) and to define the molecular mechanisms of neuronal injury in animal models of PD. The program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to the studies of neurodegenerative diseases. Their aim will be to integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contributions and achievements if each project were pursued individually. The program has one major theme: To understand the role of familial associated genes alpha-synuclein, parkin and DJ-1 in the pathogenesis of Parkinson's disease and related disorders. The role of alpha-synuclein, parkin, DJ-1 and synphilin- 1 in PD pathogenesis will be investigated using molecular, transgenic, neuropathologic, cell biologic and neurobehavioral approaches to examine the mechanism of neuronal dysfunction and injury clue to alterations in these gene products. The mechanism of neuronal loss in Parkin knockout mice and alpha-synuclein A53T transgenic mice will be characterized. We will determine whether parkin interacts with alpha-synuclein and further explore the relation between and parkin, alpha-synuclein and synphilin-1. We will explore alpha-synuclein processing and modifications and the relationship of synphilin-1 to alpha-synuclein. Furthermore, we will investigate the potential function of DJ-1 and it role in PD Pathogenesis. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neurodegeneration in genetic animal models of Parkinson's disease and the related synucleinopathies and to lead to better understanding of the function and the role of alpha-synuclein, parkin, DJ-1 and synphilin-1 in normal and pathophysiologic processes related to PD. The program consists of four projects: 1) Mouse Models of Parkin Biology and Pathobiology 2) PD Cell Models: Alpha-synuclein and Interacting Proteins; 3) Mechanisms of Neurodegeneration in Human Alpha-synuclein Transgenic Mice; 4) The Role of DJ-1 in Parkinson's Disease and four cores A) Administration and Training; B) Transgenic and Neurobehavior; C) Neuropathology and D) Clinical.